A large number of physiologically active compounds contain aromatic rings within a larger polycyclic framework (central nervous system agents, anti-tumor and antibiotic drugs, hormones, etc.). The proposal contains novel synthetic procedures for the synthesis of such molecules and their substituted and/or heterocyclic analogs. In particular, the cycloaddition of suitable dienophiles to orthodimethylene (6) and (5) annulene intermediates and the transition metal catalyzed cyclo-oligomerization of suitably constructed trisacetylenes or the co-cyclo-oligomerization of bisacetylenes with mono-acetylenes, respectively, will be investigated. The high negative heat of formation of aromatic nuclei will be utilized as a driving force for the formation of these polycycles. The proposed synthetic approach will enable extensive control over shape (five or six membered rings), nature (carbocycles, heterocylcles) and substitution of the aromatic moieties within the polycylic framework. Thus, not only naturally occurring materials will be accessible but also new modified analogs. These will be made available for testing. Synthesis of these molecules should provide information concerning structure-activity relationships, biological mechanism of drug action and new improved drugs.